Organic compound of arsenic and process for making it



Patented Oct. 5, 1943 UNITED STATES ORGANIC oMP0 UNDOF Ans NIoAnn PROCESS FOR MAKING IT Joseph George Feinberg, Brooklyn, N. Y., assignor to Parke, Davis, & Company; Detroit corporation of Michigan N o Drawin Claims. .(01

This invention, which forms a continuation-in part of my application filed May27,- 1940, Serial No. 337,445, relates generally to a .series of new organic compounds of arsenic and to processes for their manufacture, these compounds embodying certain properties which render them useful as medicinal and insecticidal agents.

One of the primary objects of this invention is to provide a method, and the reaction products thereof, wherein compounds of arsenic are combined with an alcoholamine-or a condensation product thereof, to form new compounds capable of entering into stable aqueous solution. This property would be desirablein medicinal compounds to be administeredparenterally.

A contrasting, but not contradictoryobject of this invention is to provide a method, and the reaction products thereof, wherein compound 'of arsenic are combined with an alcc-holamine, or a condensation product thereof, to form new compounds of arsenic, in liquid form, whichare insoluble .in water. Such compounds would be of definite use in the permanent impregnation of porous materials which are so employed that theyare inmore or less constant contact with water.

A more specific object of the instant invention is to provide a composition ofmatter consisting l of the reaction productof an arsenic compound and tri-isopropanolamine in an inert solvent, such as propylene glycol, as a reaction medium.

A further object of the invention isto provide a process whereby inorganic salts of arsenic may, through'chemical combination, be converted to organic compounds, which latter compounds possess none of the irritant or caustic properties that may have been inherentin the inorganic salt.

A still further object of the inventionis to treat relatively Water insoluble compounds of arsenic and so alter them through chemical combination that new compounds are produced, which latter compounds are soluble in water and are capable of forming relatively stable aqueous'solutions.

Another aim of the invention is to treat these compounds of arsenic which hydrolyze in aqueous solution to so alter them through chemical combination that new compounds are produced, which latter compounds are not hydrolyzed "in aqueous solution.

Another object of the invention is to treat compounds of arsenic to so alter them through chemical combination that now compounds are formed, which latter compounds possessphysiobyo'ther suitablesolventsl g. Application March 31,1941; r

'ScriaI No. 386,064

.2so j4',40) a v v v i p logical and therapeutic propertiesmore desirable than those of the original compounds.

Yet another object of the inventionis to prepare, through chemical combination, certain compounds of arsenic which -may beprocessed into forms suitable for medicinal purposes, either through conversion into sterileinjectible 'solution, or into forms suited for oral'administration.= e Such compounds naturally suggest them,-

selves for use in those pathological conditions wherein the properties of arsenic are of knownor suspected therapeutic value, such condition belnglreadily apparent to those skilled inhuman or? animal medicine.

i This inv ention has for aff urther aim ,topro- Vide a ,seriesof substantially homologous com,- poundswherein arsenic may be incorporated-in eitherthe trivalent or, pentavalent state. Q Ifhis achievement is of considerable importance; from a therapeutic. standpoint since it is well established that, various diseas conditions respond differently to the trivalent. and pentavalent forms of arsenic.

By way of definition, Tat term tr nsi ions" as used herein, refers tothat class of amines'in which one or more of the organic radicals contains an hydroxyl group. 7 l

The method contemplated bythisinventionim' volves the'reaction of an arsenic'compq nd with triisopropanolamine in the presence of propylene glycol." The function of the latter is merely that of a reaction-' medium and solvent for the final reaction product. This is demonstrated bythe fact that thereaction may be 'carrie'd'out in the total absence of solvent, or in theprsence of waterjethylene glycol or diethylene glycol a the solvent. Therefore, propylene'glycol is unessem tial to the process, is employed simply as 'a'fconvenien'c'e; and may be dispensed with or replaced Triisopropanola'mine is employed in the type 'proces's' since' Phave' found it most suitable for the production" of stable products; 'However, other alcoholamines-e. g. monoethanolaniine,

diethanolamine, triethanolamineiphenyl ethanolamine; phenyl diethanola'mine,- ethyl phenyl ethanolamine'or a condensation productof such .compounds-e. g. morpholine-are "capable of re acting with arsenic c ompoun'ds and may be sub- 'stituted for the triisopropanolarnine. As a matter of fact, for some commercial purposes, triethano-laminemrone of the other cheaper alcoholamines, may be preferred to triisopropanolamine. l.

e practice of the invention, it is generally ,In th tat'ionff ture of chemicals to effect or hasten reaction.

In the courseot the 'rsearch conducted, alarge number of arsenic compounds havebeen combined with triisopropanolamine by means of the type process described below. Such represent'a tive compounds as arsenic trichloride, arsenic triiodide, arsenic trioxide, arsenic acid, sodium arsenite, anaphthyl arsonic acid, 4 acetylamino l-naphthylarsonic acid, c arsonic acid, Z-nitro l-naphthylarsonic acid, 8- nitro l-naphthylarsonic acid, B-na'phthylarsonic ployed. Thus, those compounds which are originally water insoluble-e. g. arsenic trioxideyield water soluble reaction products; those compounds which are originally caustic-e. g. arsenic trichloride-yield non-caustic reaction products;

those compounds which originally hydrolyzed in aqueous solution-e. g. arsenic"dichloride-wield reaction products which do not hydrolyze in aqueous solution. Also, there appears to be a definite molar relationship between the reacting compounds in the ratio of 1 mol arsenic trioxide to 2 mols triisopropanolamine.

The finally conclusive evidence of a true chemjical ieac'tionlies in the observation I have made acid, 8-nitro 2-naphthylarsonicacid and scdium};

cacodylate have been successfully employed; "On' the other hand, certain compounds, such, astl e,

sulfide of arsenic, do not directly enter'i'nto the reaction" under the conditions employed. As a result of. this discovery Ihave reached the conclusion that compounds of arsenic are generally capable of reacting with triisopropanolamine, but the degree of: reaction is subject to the influence of the elements or radicals affixedfto: the: arsenic in the compounds used. V

w of amra tha b an of am- W will 'detail the process for combining arsenic trioxide with tinsoprepan iamme;

U. 'Sl genes s trioxide is 'ernpl d action sincethejtechnical'grade 5 c cred product) '16-g'ms.'of so opano lamine are addedto 20, c. c. of propylene g coll'and sormine 9K1 a was: a h o t e ui e ou ce, i ilt To. pret it as: sible decomposifolnfoif the'reaction product. it is adv se. 1e il e the em er te elwi 9D. '0- throughout the, process; To, the, mixture. is "added 2.5 gins. of arsenfc trioxide the, mixture is stirred until thearsenic trioxide is dissolved. The resultant product is filtered 'throughrfilter paper, using a Buchner funnel and suction. The filtrate, is stored in amber glass bottles and represents th e t d fi d ss ve i e m x ur of propylene glycol and excess, unreacted "an isopropanolamine.

ome ommen s c a e c re r a i r su i te d n e e e r mear et h queni le v i these o he e' es u ds a w l contai amounts of arsenic equivalent to that contained in rsen ox s- Ho ev r I wi h. t emp asi hat t e i =i r v I a e empl yed in t e b v pr cess a e' iot r t a but are ar i rari r ho n for conveni e- As a matt r o fa i com e cial application of the invention, it will probably be deemed advisable to, raise the ratio of arsenic t r isq r uano amme, since t e triisopropanoition, is involved is bor'ne out by several 'obfservatime? I h read d ceased i ie' e' e e cases considerable heat isevolved, which, though amine.

infthosfe cases where a readily identifiable byproduct of the' reaction is formed, in that I have detected, this by-product upon completion of the reaction. Thus, when arsenic trichloride is reacted with triisopropanolamine, the odor of hydrogen chloride'is very strong. In this case, too, needle-like white crystals separate on standing, said crystals having been identified as the hydrochloride of the excess, unreacted' triisopropanol- The formation of'hydrogen chloride in this'case points definitely to a double decomposition reaction with the eliminatic'in of a chloride ion from the metal chloride and. the elimination of a hydrogen ion from" the triisopropanolamine.

The resultant reactionproducts are complex in nature and their ultimate chemical composition has not been determined,but I have observed and noted ce'rtain'of their'characteristics. Though the properties of the reaction products are, naturally, somewhat dependent upon the 'original arsenic compound and alcoholamine-employ'ed in the reaction, the following general observations maybemade: M

Whenpife'pared'in accordance-with the type processpresented above, the resultant product is a somewhat" viscous liquid which retains 'the'haracteristi'c' odor of the triisopr'opan'olamine, 'the latter being present in excess, except where this odor is obscured by the acrid odor of liberated hydrogen chloride. The color ranges from "the not conclusive evidence, tends to point to'a chemical reactiontaking place. Further evidence of properties of the original arsenic 'cornpoundsemchemil himp! is h e ie aiinct eri in i light straw color obtainedwhen arsenictri'oxide is employed, to the deep'arnber color obtained when Z-nitro l-napl'ithyl arsenic acid is Y em q 7..

"'I'he'solubility of these compounds in water depends upon the solubility of the alcoholamine employed( Generally, those arsenic compounds pre pared 'from alcoholamines containing only alkyl radicals are readily soluble in absolute alcohol, acetone, glycerine and chloroform, but only slightly soluble in ether and toluene. Their aqueous solutions are not decomposed by boiling and are compatible with blood plasma. Again by way of example ratherfthan by way of limitation, I have'demonstrated that as much as 5 c. c. of an aqueous solution of triisopropanolamine ap senic trioxide, containing /3 gr. of arsenic per 0. c.,-may be injected intravenously into a meclium size dog at one time without producing any ill effects. Smaller doses have been given daily over a period of time with no impairment of the health of the dog. 7

On the other hand, reaction products of arsenic compounds and alcoholamines co'ntainihg one or more aromaticgroups are generally insoluble in water. Far from being" an undesirable property, this insolubility in water may be most desirable for certain specific purposes e. im-

pregnation of porous materials which of necessi- Having thus described the invention, I claim:

1. A method of producing a composition of matter of the character described, which consists in adding arsenic trioxide to triisopropanolamine and heating the mixture until the reaction is completed.

2. A method of producing a composition of matter of the character described, which consists in adding arsenic trioxide to a mixture of triisopropanolamine and propylene glycol, and heating the Whole until the reaction is completed.

3. A composition of matter consisting of the reaction product of arsenic trioxide and triisopropanolamine.

4. A composition of matter consisting of the reaction product of arsenic trioxide and triisopropanolamine in propylene glycol.

5. A method of producing a composition of matter of the character described, which consists in bringing together an acidic compound of arsenic of the class oxygen and halogen compounds of arsenic wherein the acidic oxygen and en atoms are direct y attached to the arsenic and an amine of the class hydroxy alkyl amines and N-aryl substituted hydroxy alkyl amines and allowing the two to react spontaneously.

6. A method of producing a composition of matter of the character described, which consists in bringing together an acidic compound of arsenic of the class oxygen and halogen compounds of arsenic wherein the acidic oxygen and halogen atoms are directly attached to the arsenic and an amine of the class hydro-Xi; alkyl amines and N-aryl substituted hydroxy alkyl amines and applying heat to the mixture until the reaction is completed.

7. A method of producing a composition of matter of the character described, which consists in reacting in the presence of an inert solvent an acidic compound of arsenic of the class oxygen and halogen compounds of arsenic wherein the acidic oxygen and halogen. are directly attached to the arsenic and amine of the class hydroxy alkyl amines and N aryl substituted hydroxy alkyl amines.

8. A composition consisting of a reaction product of the process of claim 5.

9. A composition consisting of a reaction prodnot of the process of claim 6.

10. A composition consisting of a reaction product of the process of claim 7.

JOSEPH GEORGE FEINBERG. 

